DE3541165C2 - - Google Patents

Description

The invention relates to a device for continuous transcutaneous in vivo determination of concentra changes in blood, especially for determination of the glucose content, with a broadband radiation source, de Ren light shines through the measuring point and from one Detector arrangement for determining the substance-specific Absorption is detected.

Such a device for determining glucose concentration in a patient's blood is from DE 27 24 543 A1 known and has a radiation source that emits light of only one wavelength. To Passage through the measuring point crosses the light a filter to avoid possible interference from stray light turn off. The detector arrangement sets the light signal into an electrical signal, which after ampl Kung is supplied to a display device. If in one such an arrangement the absorption of glucose in vivo should be recorded, it turns out that for practice required long-term stability and accuracy are not feasible. In particular, there are disturbances rende intensity fluctuations in that the thickness of a patient's earlobe clamped in an ear clip periodically changed according to the pulse rate changed, which periodically changes a glucose concentration is faked. Other instabilities result differs in that the light source during operation of several hours in their radiation intensity changed.  

DE 27 41 981 A1 describes a method together with a device for determining the acid substance content in the blood described, in which the influence of confounding factors by use of three measuring frequencies is largely switched off, but the measurement performed in the blood by means of an inserted catheter in the reflection process becomes.

DE 26 37 501 A1 discloses a device for measuring a substance concentration in the blood, in which the optical absorption capacity of an indicator solution is evaluated is, into the substances from the blood through the skin and a membrane of the measuring device diffuse into it. But again there is no radiation of the measurement place (transcutaneously) instead.

EP 00 30 610 B1 discloses a method and device in which the concentration tion of optically active substances is determined by a polarimetric measurement. The effect of the rotation of the plane of polarization is linearly polarized measurement light exploited by the optically active substances. However, this procedure is not suitable for transcutaneous use on the earlobe because of the multiple scatter in the tissue largely removed the preferred direction of polarized light will.

The closest prior art to the invention is open in EP 01 60 768 A1 beard. For the transcutaneous measurement of the glucose content of the blood, light is ver different wavelengths are used, each in the absorption range of glucose or the tissue. However, this can also influence the measurement results nisse for example by the described change in thickness of the earlobe can be prevented safely.

In contrast, the invention is based on the object, one from EP 01 60 768 A1 Known device for the continuous transcutaneous in vivo determination of Changes in the concentration of blood continue to develop in such a way that over a long period of time a continuous determination of small changes in concentration despite changes the layer thickness of the measurement object and the intensity fluctuations of the light source is possible with high accuracy.

This object is achieved by the features of claim 1.  

The detector arrangement has at least one of the Radiation of the light channels illuminates the detector, the output signal of the individual light channels arranged lock-in-ver synchronized with the choppers feeds more, whose the individual light channels assigned output signals to an evaluation circuit beat.

An even higher sensitivity using the through z. B. glucose will then cause refraction achieved when the detector array has a variety of Has detector elements that are rotationally symmetrical to the optical axis of the one leaving the measuring point Light beam as a disc-shaped central element with concentric ring elements are designed, the Central element and each ring element evaluation units with lock-in-ver designed for each light channel are assigned to strengths.

The evaluation of three from a single radiation source of outgoing light channels allowed in addition to Compensation detection of a substance concentration that were influenced by different layer thicknesses Changes in intensity as well as those caused by instabilities changes in intensity caused by the light source. On  this way, very small changes in concentration can be reliably detected, including one determination of concentration over hours or an in vivo monitoring of the glucose concentration in the A patient's earlobe is possible.

Appropriate training and refinements of Invention are characterized in the subclaims.

The invention is based on in the drawing tion illustrated embodiments in more detail tert. It shows:

Fig. 1 shows an embodiment of the invention with three light channels and a single detector

Fig. 2 shows an embodiment of the invention with three light channels, and a plurality of concentrically arranged annular Detek gate elements for detecting the measurement point, the exiting light,

Fig. 3 shows an embodiment of the invention with four light channels and a single detector and

Fig. 4 shows an exemplary embodiment of the invention with four light channels and a detector detecting the light distribution from a plurality of concentrically arranged annular detector elements.

The device shown in Fig. 1 for continuous transcutaneous in vivo determination of concentration changes or for transcutaneous in vivo monitoring of the glucose content in the blood of a patient has a radiation source 1 , which can be, for example, a halogen lamp. The light from the radiation source 1 arrives at a chopper wheel with three different segmentations, which form a first chopper 2 , a second chopper 3 and a third chopper 4 , via an optic with three lenses, not shown in the drawing. The broadband light emerging from the lenses of the radiation source 1 is interrupted by the choppers 2 to 4 regularly and overlapping. The geometric arrangement can be chosen such that the three lenses illuminating the chopper wheel are arranged in a triangle. The segmentation of the chopper wheel is different for each of the drawing in Fig. 1 and from the broadband radiation source 1 outgoing light beam, for. B. seventeen times, eleven times and simple, a seventeen times segmentation means that seventeen openings and seventeen covers are provided in the chopper wheel. In order to reduce interferable harmonics, a prime number ratio is preferred for the segmentation of the chopper wheel. The chopper 2 , 3 and 4 forming segments on the chopper wheel are assigned light barriers through which control signals are generated, the frequencies of which are assigned to the chopper frequencies of the chopper 2 , 3 and 4 . The control signals of the choppers 2, 3, 4 are coupled out via lines 5, 6, 7 .

The choppers 2, 3, 4 form the first elements of three light channels with different wavelengths and different modulation frequencies defined by the choppers 2, 3, 4 .

The light fed by the chopper 2 into the first light channel arrives at an interference filter 8 , the transmission wavelength of which is layer-specific or is 805 nm. Light of this wavelength is weakened when crossing blood depending on the number of red blood cells in the light path, regardless of the glucose concentration. For this reason, light with a wavelength of 805 nm is used to detect changes in the effective layer thickness of the blood.

Part of the light from the broadband radiation source 1 passes through the chopper 3 to a second interference filter 9 , the transmission wavelength of which is in the range of low absorption of the measurement sample or around 1300 nm. Glucose absorbs only weakly in this area, which is why the light in the second light channel can be used to detect changes in device parameters, such as those of the light intensity.

The third chopper 4 assigned third Inter reference filter 10 has a transmission wavelength in the range of an absorption band of the substance to be monitored, for. B. of 1600 nm. This range covers an absorption band of glucose.

The third interference filter 10 can be designed such that the transmission wavelength is changed periodically with a predetermined frequency of, for example, 1 kHz. Such a wavelength modulation, which is tuned to 1.1 times the half-width of the absorption band, allows the realization of the methods known from derivative spectroscopy. The modulation frequency of 1 kHz must be considerably higher than the chopper frequencies mentioned above. The use of derivative spectroscopy makes it possible to carry out a particularly sensitive and stable concentration measurement, in particular of glucose, in the third light channel. A signal corresponding to the modulation frequency is coupled out via a line 11 .

Radiation sources of different wavelengths chopped at different frequencies are available at the outputs of the interference filters 8, 9 and 10 . The light from the three light channels is fed behind the interference filters 8, 9, 10 into optical waveguides 12, 13, 14 and with the aid of them leads to a measuring arrangement 15 , which is designed in a manner known per se in particular as an ear clip that is placed on a patient's earlobe is pinched. The output ends of the optical fibers 12, 13, 14 are directed in the measuring arrangement 15 to the center of the measuring point, in particular the earlobe. The light emerging from the measuring point, which contains light from all three light channels, arrives in the exemplary embodiment shown in FIG. 1 at a single detector 16 , the output signal of which, via a amplifier 17 assigned to the three light channels, lock-in amplifiers 18, 19, 20 feeds. The clock signals generated by the choppers 2 , 3 , 4 reach the lock-in amplifiers 18 , 19 , 20 via the lines 5 , 6 , 7 and in this way allow the signals assigned to the three light channels to be separated.

The output of the amplifier 17 is also connected to the input of a boxcar amplifier 21 (amplifier with gate circuit), the output signal of which feeds a further lock-in amplifier 22 . The lock-in amplifier 22 receives via the line 11 and a Fre quenzverdopplerschaltung 23 clock signals having twice the frequency with which the transmission wavelength of the interference filter 10 for derivative spectrometry is wobbled.

The output signals of the lock-in amplifiers 18, 19, 20 and 22 are digitized via analog-digital converters (not shown in the drawing) and reach a measured value memory 24 .

The selection electronics 25 connected upstream of the measured value memory 24 is framed in dashed lines in FIG. 1. The selection electronics 25 delivers a first signal to the measured value memory 24 , which is assigned to the effective layer thickness, in particular of the blood in the measuring arrangement 15, and thus to the respective non-constant earlobe thickness. The second signal provides a measure of the respective intensity of the radiation source 1 , so that when the intensity of the radiation source 1 changes, corrections for the other signals can be derived from this signal in order to prevent an increase in the radiation source 1 as the intensity decreases Absorption is displayed as the measurement result. The absolute changes in the substance concentration or the glucose level are indicated by the third output signal of the selection electronics 25 , while the fourth measurement signal generated with the aid of the derivative signals represents a measure of the relative changes in concentration, in particular the fluctuations in glucose.

The first three signals would be sufficient for many applications, but not for the determination of low concentrations or the high-precision measurement of glucose in the blood of the earlobe, because the absorption is weak and because apart from the absorption, the refraction of the light in the measuring point or on glucose molecules also plays a role . Because of the refraction that occurs, it is expedient to supplement the device shown in FIG. 1 and intended for measurement in the case of scattering without refraction in the manner shown in FIG .

In the exemplary embodiment of a device for measuring the absorption in the case of scattering with refraction shown in FIG. 2, the same reference symbols have been used for corresponding components. The light away from the radiation source 1 via the three light channels to the measuring arrangement 15 corresponds to the embodiment shown in FIG. 1. However, the light leaving the measuring arrangement 15 does not irradiate a single detector, but rather a ring detector which detects the light bundle emerging behind the measuring arrangement 15 diver gent and allows the light distribution in the light bundle and changes in the light distribution in the light bundle to be detected. The ring detector consists for example of a central disc-shaped photosensitive element and several, for. B. four, concentrically arranged around this annular detector elements. Such a ring structure can also be formed, for example, by diode cells or a diode matrix. The ring detector is arranged behind the sample holder 15 concentrically to the outgoing measuring beam and supplies for its central element and its four rings surrounding it output voltages which are conducted via lines 26 to evaluation units 27 . Each of the Auswerteein units 27 corresponds to the evaluation unit framed in phantom in FIG. 1, 27. In this way, it is possible through the large number of evaluation units 27 not only to detect changes in intensity in the range of the transmission wavelengths of the interference filters, but also changes in the intensity distribution, which can be attributed to, for example, a refraction-related refraction.

The signals from the evaluation units 27 reach a summing circuit 28 and from there to a display unit 29 . In the example shown in FIG. 1, the output of the evaluation unit 27 is directly connected to the display unit 29 .

In addition to the measured value memory 24 , each evaluation unit 27 contains a calibration memory 30 with a calibration table, an evaluation circuit 31 and a calibration evaluation device 32 . In addition, each evaluation unit 27 has an initial value memory 33 . The calibration values required for calibration are illustrated in FIGS. 1 and 2 by the box labeled 34 .

The evaluation of the measurement signals for glucose is discussed in more detail below. The measuring beam emerging from the optical waveguide end 14 is generally rotationally symmetrical. The same applies to the intensity I of the light impinging on the detector of the measuring device. An increase in the concentration of glucose would, as expected, bring about a uniform weakening in intensity, while a decrease in concentration would initially lead to a steady increase in intensity. Surprisingly, however, the absorption effect overlaps with a refraction effect through which the light is also deflected depending on the concentration. As a result, the absorption may appear to increase or decrease. The intensity changes caused by the superimposition of both effects are detected by evaluating the signals present on the lines 26 of the various concentrically arranged ring elements of the ring detector.

Each evaluation unit 27 therefore contains the initial value memory 33 for the output intensities I _i ° and it averages i = 1 for the individual ring elements. . . 5 the respective relative intensity ratios I _i / I _i °, which are a proportional measure of the change in the concentration of glucose.

The goal of processing the various signals is the most accurate determination of the changes in intensity for any time. The calculation process is like follows: For the evaluation of the derivative signal is according to N. Hager and R. Stäudner (technical measuring 43 1976 pp. 329-364) the determination of the concentration proportional expression

required. Are the signals falling on the i- th ring of the ring detector for the first light channel (805 nm) with S 1 _i , for the second light channel (1300 nm) with S 2 _i , for the third light channel with S 3 _i and for the channel of the derivative spectrometer with S 3 D _i , the following applies:

While d² I / d λ ² corresponds to the signal S 3 D _i , I S 3 _i can be used instead of as long as the device parameters and the measuring layer thickness remain constant. Non-constant ratios can be detected in that I with the factor S 1 _i ° / S 1 _i as an approximation for small changes in the measuring layer thickness and the factor S 2 _i / S 2 _i ° for device parameter changes, especially the lamp intensity multiply is. Then the change in concentration of glucose Δ C _iG calculated as respective relative value of

where the index ° represents the stored initial value. These values Δ C _iG can Mes within a solution in the center of the radiation positive and negative to be out of the center or vice versa. Therefore, the change in concentration Δ C _{G is} sought

These values are relative values and must have a other method can be absolutely calibrated.

The hardware for these arithmetic and calibration operations is illustrated in FIG. 1 for a one-element detector arrangement in which there is no spatial resolution of the radiation if the refractive index has an insignificant influence on the absorption measurement. For this case, a single detector element 16 is attached in place of the ring detector mentioned above in Fig. 1 behind the sample holder 15 .

In the embodiment shown in FIG. 2, the initial values S 1 ₁ °, S 2 ₁ °, S 3 ₁ ° and S 3 D ₁ ° are retrieved from the selection electronics 25 and stored in the initial value memory 33 . The calibration memory 30 contains the calibration values, which are supplied externally by using another, already established method 34 , and the associated measured values S 1 ₁ ^k , S 2 ₁ ^k , S 3 ₁ ^k and S 3 D ₁ ^k . Both sets of values with the indices ° and ^k are taken from the measured value memory 24 , which contains the current measured values S 1 ₁, S 2 ₁ S 3 ₁ and S 3 D ₁. From the values contained in the measured value memory 24 and the initial value memory 33, a relative value for the change in the glucose concentration is determined in the evaluation circuit 31 using the above equation (2) with i = 1. The glucose concentration is determined in the calibration evaluation device 32 from the comparison with the calibration values from the calibration memory 30 and is displayed with the aid of the display unit 29 . The dash-dotted lines in Fig. 1 boxed evaluation unit 27 is used in the element shown in Fig. 1 embodiment only for the existing detector 16 and in the illustrated in Fig. 2 embodiment, for each ring.

For samples such as glucose in the blood, which not only influence absorption but also noticeably affect the refraction of the light, the detected radiation is expediently spatially resolved, for example by using a ring detector with five elements (i = 1 ... 5). For such a ring detector arrangement, the data is evaluated using several evaluation units 27 according to FIG. 2. The input part with the radiation source 1 , the choppers 2, 3, 4 with the light barriers, the interference filters 8, 9, 10 and the sample holder 15 does not differ from the single-detector arrangement according to Fig. 1. Instead of a single detector are however, in the Ausführungsbei game of FIG. 2 five detector elements used, the signals are processed in evaluation units 27 separately or in parallel, the relative values in the summing circuit 28 summed up according to equation 3 and displayed in the display unit 29 .

While the exemplary embodiments of the invention shown in FIGS . 1 and 2 are intended to monitor a single substance, FIGS . 3 and 4 show exemplary embodiments of the invention which permit the monitoring of two substances in the test sample. From the following description it is also readily apparent to the person skilled in the art that the device for the continuous determination of concentration changes in substance mixtures can also be expanded such that not only two substances but a large number of substances in a substance mixture can be monitored if for a light channel is provided for each substance, the filter of which lies in the region of the absorption band of the substance to be monitored.

In the examples shown in FIGS . 3 and 4, the parts already known from FIGS . 1 and 2 are provided with the same reference numerals. In the case of blood tests, the measuring arrangement 15 can be designed as an ear clip which is clamped onto the earlobe of a patient. Here, for example, the device shown in Figs. 3 and 4, in addition to monitoring of the glucose in the blood by adjusting the third inter-ference filter 10 allows a transmission wavelength of 1600 nm in addition the patient's blood to the cholesterol content to check if a further interference filter 60 is used in the manner shown in Fig. 3 to provide an additional light channel with a transmission wavelength of 1710 nm between the radiation source 1 and the measuring arrangement 15 be.

The light channel assigned to the cholesterol receives the light from the radiation source 1 via a fourth chopper 54 , the chopper frequency of which differs from the chopper frequencies of the choppers 2 to 4 , so that a separation of the signal in the evaluation unit 27 is possible.

Control signals of the chopper 54 are coupled out via a line 57 . As can be seen in FIG. 3, these control signals reach a lock-in amplifier 70 and another box car amplifier 71 . The output of the boxcar amplifier 71 is connected according to the boxcar amplifier 21 with a lock-in amplifier 72 to which 73 clock signals are supplied via a frequency doubler. For this reason, the fourth interference filter 60 is electrically connected via a line 61 to the input of the frequency doubler 73 , so that a derivative spectrometry can also be carried out in the additional channel provided for the cholesterol detection. In Fig. 3 it can be seen further down an optical fiber 64 is passed through the light after passing through the fourth interference filter 60 to the measuring arrangement 15 °.

While FIG. 3 shows an extension by a fourth light channel or a second measuring channel compared to FIG. 1, FIG. 4 shows an extension of the measuring range for the arrangement shown in FIG. 2 and, like this arrangement, permits an evaluation of the spatial light distribution of the Sample holder 15 leaving light. Also in Fig. 4, components that match the components in Fig. 2 are provided with the same reference characters. To implement the second measuring channel or the fourth light channel, it can be seen that the exemplary embodiment according to FIG. 4 has, in addition to the fourth chopper 54 and the fourth interference filter 60, evaluation units 27 which, instead of six inputs as in FIG. 2, each have eight inputs. The two additional inputs of the evaluation units 27 correspond to the lines 61 and 57 , which have already been discussed in connection with FIG. 3. The evaluation of the various signals in the device shown in FIG. 4 is carried out analogously to the evaluation in the device in accordance with FIG. 3, but the channel assigned to the cholesterol is additionally monitored with a transmission wavelength of 1710 nm.

As already mentioned, it is possible to expand the arrangements described above by additional channels or to use the choice of the different transmission frequencies to monitor substances other than glucose and cholesterol in the blood. The respective transmission wavelengths for the interference filters 8 to 10 and 60 can easily be determined directly from the absorption bands of the substances present in the substance mixtures or determined experimentally if the transmission behavior of the substance mixtures is still unknown.

Claims (11)

1. Device for the continuous transcutaneous in vivo determination of concentration changes in the blood, in particular for determining the glucose content, with a broadband radiation source, the light of which shines through the measuring point and is detected by a detector arrangement for determining the substance-specific absorption, characterized in that the light Via optics into several light channels, each with a chopper ( 2, 3, 4, 54 ) with an individual frequency, each with a filter ( 8, 9, 10, 60 ) with a certain transmission wavelength and each with an optical fiber ( 12, 13 , 14, 64 ) in the measuring point ( 15 ) is coupled in that the output signal of the detector arrangement ( 16 ) above the light channels is assigned to the chopper frequencies coordinated lock-in amplifier ( 18, 19, 20, 22, 70, 72 ) is connected via a measured value memory ( 24 ) to an evaluation circuit ( 31 ), and that the transmission wavelength of the first filter ( 8 ) in an area that is mainly sensitive to the measuring layer thickness, that of the second filter ( 9 ) in an area where the measuring point absorbs only weakly, and that of the other filters ( 10, 60 ) lies in the area of the absorption bands of the substances whose changes in concentration determine should be. 2. Device according to claim 1, characterized in that the detector arrangement has at least one detector ( 16 ) illuminated by the radiation of all light channels, the output signal of which is assigned to the individual light channels and is synchronized with the choppers ( 2, 3, 4, 54 ). in amplifier ( 18, 19, 20, 22, 70, 72 ) feeds whose output signals assigned to the individual light channels from a measured value memory ( 24 ) act on an evaluation circuit ( 31 ). 3. Apparatus according to claim 2, characterized in that the detector arrangement has a plurality of detector elements which are designed rotationally symmetrical to the optical axis of the measuring point ( 15 ) leaving the light beam as a disk-shaped central element with concentric ring elements, and that the central element and each ring element ( 26 ) are assigned to evaluation units ( 27 ) with lock-in amplifiers ( 18, 19, 20, 22, 70, 72 ) designed for each light channel ( FIGS. 2, 3 and 4). 4. The device according to claim 3, characterized in that the results for the individual ring elements ( 26 ) detecting evaluation units ( 27 ) to a summing circuit ( 28 ) are closed, the output of which feeds a display device ( 29 ). 5. Device according to one of the preceding claims, characterized in that the radiation source ( 1 ) is a halogen lamp. 6. Device according to one of the preceding claims, characterized in that the optical fibers ( 12, 13, 14 ) are coupled to an ear clip for plugging onto the earlobe of a patient, the output signal of which feeds the detector arrangement ( 16 ), and that for monitoring the Glucose concentration in the blood, the transmission wavelength of the filters ( 8, 9, 10 ) is 805 nm for the first, 1300 nm for the second and 1600 nm for a third light channel. 7. Device according to one of the preceding claims, characterized in that the third Light channel a first substance to be monitored and a fourth light channel to oversee a second is assigned to the corresponding substance. 8. Device according to one of the preceding claims, characterized in that the filters ( 8, 9, 10, 60 ) are interference filters. 9. Device according to one of the preceding claims, characterized in that the filter ( 10, 60 ) assigned to the absorption band of the substances to be detected are periodically detuned, the assigned light channels being an arrangement for the derivative spectrometry ( 11, 21, 22, 23, 61, 71, 72, 73 ). 10. Device according to one of claims 2 to 8, characterized in that the evaluation units ( 27 ) have a calibration memory ( 30 ). 11. Device according to one of the preceding claims, characterized in that the choppers ( 2, 3, 4, 54 ) are formed by segments on a common chopper wheel.